Adhesions are attachments between the surrounding organs or tissues that are normally separate from one another, resulting from excessive generation of fibrous tissues or extravasation and clotting of blood during healing of wounds including traumas caused by inflammation, cut, chafing, surgery or the like. Adhesions may arise after any kind of surgical operations and may cause serious clinical sequelas due to attachments between organs or tissues around the surgical regions, during post-operative healing.
Generally, the incidence of post-operative organ adhesions is reportedly in a range of 55% to 93% (Ann. Royal Coll. Surg. Engl., 75, 147-153, 1993). A large percentage of abdominal surgeries result in adhesions. Although some of these adhesions may undergo spontaneous decomposition, adhesions still remain in most cases even after healing of wounds, which may result in a variety of sequelas. The kind of sequelas is very various. According to the US statistical data, it is known that post-operative adhesions entails, as main symptoms, 49% to 74% of enterocleisis, 15% to 20% of infertility, 20% to 50% of chronic pelvic pain, and 19% of enterobrosia in a subsequent surgery (Eur. J. Surg., Suppl 577, 32-39, 1997).
The mechanism of intraperitoneal adhesion formation is specifically described in the paper published by Granger (Infert. Reprod. Med. Clin. North Am., 5:3, 391-404, 1994). According to Granger, adhesions are initiated by fibrin resulting from the clotting process of blood among exudates generated after surgeries. The inflammatory exudate is rich in fibrin which forms a clot of blood on wound surfaces. As fibrin is degraded, mesothelium is regenerated, which normally results in healing of wounds. The decomposition of fibrin or fibrinolysis is dependent on the conversion of plasminogen to plasmin which is a fibrinolytic enzyme, and this reaction is promoted by a tissue plasminogen activator (tPA) existing in the mesothelium and the underlying stroma. However, if fibrinolysis does not occur, inflammatory cells and fibroblasts infiltrate into the fibrin matrix to result in organized adhesions. In this manner, adhesions take place through a series of the fibrinogenesis mechanism and the fibrinolysis mechanism, and the relationship between both mechanisms is not simple and is closely related to the healing process of wounds.
As one of various methods for preventing such adhesions, intensive research has been focused on an anti-adhesion agent that prevents the formation of adhesions between the adjacent tissues, through the formation of a physical barrier during healing of wounds of tissues using a barrier, as similarly in the action of a surfactant. The anti-adhesion barriers used for these barriers may be broadly divided into two classes in view of their types: one is a membrane type barrier including a film type, a non-woven type and a sponge type, and the other is a solution type barrier including a gel type.
Examples of the membrane type anti-adhesion material include oxidized-regenerated cellulose, expanded polytetrafluoroethylene (hereinafter, referred to as “ePTFE”), films made up of modified hyaluronic acid, sodium carboxymethyl cellulose and chemical modifying agents, and the like.
Examples of the solution type anti-adhesion material include a lactated Ringer's solution, a dextran-70 solution, a heparin solution, a sodium carboxymethyl cellulose solution, a hyaluronic acid solution, a chondroitin sulfate solution, a polyethylene glycol solution, a poloxamer solution, and the like. Among these solution type anti-adhesion materials, a lactated Ringer's solution, a dextran-70 solution, a heparin solution and the like have a main mechanism which, during healing of the peritoneum, induces fibrin-covered surfaces to move away from each other. Although they are preparations which have been used to inhibit adhesions by separating tissues from each other, satisfactory anti-adhesion effects are not achieved due to their rapid absorption into the peritoneum (Am. Surg., 63, 775-777, 1983). Meanwhile, since polyethylene glycol and the like are not degraded in vivo, only a low-molecular weight material that can be discharged through a metabolic pathway when absorbed can be used. However, the use of such a low-molecular weight material results in excessively rapid absorption, so that it cannot serve as an effective barrier to prevent adhesions for an extended period of time.
Meanwhile, hyaluronic acid disclosed in U.S. Pat. No. 4,141,973 is a linear macromolecular polysaccharide consisting of alternately bonded β-D-N-acetylglucosamine and β-D-glucuronic acid and is known to exhibit excellent biocompatibility even when it is transplanted or infused in vivo. However, also due to in vivo decomposition and absorption within a relatively short period of time, there is a limitation in terms of performance as an anti-adhesion agent.
As an attempt to improve such disadvantages, U.S. Pat. No. 6,387,413 B1 discloses a preparation of a hyaluronic acid gel composition by adding a polymer compound such as carboxymethyl cellulose, for the purpose of supplementing properties of hyaluronic acid gel in terms of physical properties.
As described above, a variety of investigations has been made to supplement properties of hyaluronic acid gel in terms of physical properties. Among others, in order to improve disadvantages of hyaluronic acid in terms of being readily water-soluble upon in vivo applications and relatively short in vivo retention time, various modifications of hyaluronic acid have been proposed which is modified by a variety of chemical crosslinking agents or chemical modifying agents.
Although the materials thus developed up to date present potentialities for the prevention of adhesions, since chemical crosslinking methods are largely employed, there are problems associated with inconveniences of removing crosslinking agents or additives and complicated processes in conjunction with problems of toxicity and safety.
As a result of a variety of extensive and intensive studies and experiments to solve the problems as described above, that is, problems associated with low efficiency of anti-adhesion function, synthesis of chemical crosslinking agents or additives, and possible residual toxicity, the inventors of the present invention discovered that it is possible to solve the above-described problems by providing a composition including a high-molecular weight hyaluronic acid with optimized biocompatibility without the use of a chemical crosslinking agent. The present invention has been completed based on these findings.
Further, unlike conventional products including a simple mixture of polymeric materials that serve as physical barriers in terms of anti-adhesion effects, the present invention is based on a new functional approach of adhesion prevention wherein the use of hyaluronic acid and hydroxyethyl starch in the present invention not only functions as a physical barrier, but also inhibits thrombus formation which is basically responsible for the incidence of adhesions. Therefore, the present invention can be distinguished from conventional products and is also confirmed to be excellent in terms of anti-adhesion effects and safety.